The heme oxygenase (HO) system is essential for heme and iron homeostasis and necessary for adaptation to cell stress. HO degrades heme to biliverdin (BV), carbon monoxide (CO) and ferrous iron. Although mostly beneficial, the HO reaction can also produce deleterious effects, predominantly attributed to excessive product formation. Underrated so far is, however, that HO may exert effects additionally via modulation of the cellular heme levels. Heme, besides being an often-quoted generator of oxidative stress, plays also an important role as a signaling molecule. Heme controls the anti-oxidative defense, circadian rhythms, activity of ion channels, glucose utilization, erythropoiesis, and macrophage function. This broad spectrum of effects depends on its interaction with proteins ranging from transcription factors to enzymes. In degrading heme, HO has the potential to exert effects also via modulation of heme-mediated pathways. In this review, we will discuss the multitude of pathways regulated by heme to enlarge the view on HO and its role in cell physiology. We will further highlight the contribution of HO to pathophysiology, which results from a dysregulated balance between heme and the degradation products formed by HO.

Differentiation of porcine T helper cells is still poorly investigated, partly due to a lack of monoclonal antibodies (mAbs) specific for molecules involved in this process. Recently, we identified a mAb specific for porcine CD27 and showed that CD27 is expressed by all naïve CD8α^- T helper cells but divides CD8α⁺ T helper cells into a CD27⁺ and a CD27^- subset. In the present study, detailed phenotypical and functional analyses of these T-helper cell subpopulations were performed. Naïve CD8α^-CD27⁺ T helper cells predominantly resided in various lymph nodes, whereas higher proportions of CD8α⁺CD27⁺ and CD8α⁺CD27^- T helper cells were found in blood, spleen and liver. Both CD8α⁺CD27⁺ and CD8α⁺CD27^- T helper cells were capable of producing IFN-γ upon in vitro polyclonal stimulation and antigen-specific restimulation. Experiments with sorted CD8α^-CD27⁺, CD8α⁺CD27⁺ and CD8α⁺CD27^- T-helper cell subsets following polyclonal stimulation revealed the lowest proliferative response but the highest ability for IFN-γ and TNF-α production in the CD8α⁺CD27^- subset. Therefore, these cells resembled terminally differentiated effector memory cells as described in human. This was supported by analyses of CCR7 and CD62L expression. CD8α⁺CD27^- T helper cells were mostly CCR7^- and had considerably reduced CD62L mRNA levels. In contrast, expression of both homing-receptors was increased on CD8α⁺CD27⁺ T helper cells, which also had a proliferation rate similar to naïve CD8α^-CD27⁺ T helper cells and showed intermediate levels of cytokine production. Therefore, similar to human, CD8α⁺CD27⁺ T helper cells displayed a phenotype and functional properties of central memory cells.